A new estrogen drug for hormone therapy in prostate cancer; early results

This Phase II (early phase) study aimed to evaluate the safety and side effects of GTx-758, a drug that is being researched as a therapy for lowering testosterone levels in the blood stream.

Androgen-deprivation therapy (ADT – a form of hormone therapy that lowers testosterone levels) remains the most effective treatment for advanced prostate cancer. However, lowering testosterone levels via ADT can also result in decreasing levels of estrogen, leading to side effects such as decreasing bone strength, hot flashes and breast tenderness. Drugs that affect estrogen levels have also been used as a form of ADT in treating prostate cancer, as these drugs help to avoid the side effects associated with estrogen deficiency. Among these therapies, GTx-758  is a drug that interacts with proteins on cell surfaces similarly to normal estrogen. 

The authors aimed to evaluate the effectiveness of GTx-758 compared to leuprolide (Eligard, Lupron; drugs that decrease the levels of testosterone in the body, as well as the levels of estrogen) in lowering testosterone levels while avoiding the side effects associated with decreased estrogen levels. 

159 men diagnosed with advanced prostate cancer were out into three groups: Group 1 received 1000 mg of GTx-758 orally daily (53 patients), Group 2 received 2000 mg of GTx-758 orally daily (55 patients) and Group 3 received a leuprolide injection (51 patients).  Each subject was followed up for 60 days; those who had achieved adequately low levels of testosterone (castration) were further followed up to 360 days to assess safety and side effects of GTx-758.  

Treatment reduced total testosterone to < or equal 50 ng/dl by day 60 in 43.4% patients who received 1000 mg of GTx-758, 63.8% patients who received 2000 mg GTx-758  and 88.2 % of patients who received leuprolide.  However,  levels of free testosterone (this is the testosterone available in the blood to exert an effect on the body) were 0.4 pg/ml in those receiving 1000 mg GTx-758 and 0.3 pg/ml in those receiving 2000 mg GTx-758, compared to 0.9 pg/ml in those receiving leuprolide at day 60. 

By day 28, 25% of men treated with 1000 mg of GTx-758 had experienced hot flashes, compared to 12.8% of men treated with 2000 mg of GTx-758 and 60.4%  of men treated with leuprolide.  By three months, compared to the beginning of the study, those who were taking leuprolide had increased levels of proteins in the blood that indicate weakening of the bones. At the same time point those taking GTx-758  had lower levels of these proteins compared to the beginning of the study. 

Those taking any dose of GTx-758 had a higher rate of serious adverse events including blood clots deep within the veins (6% of those taking 1000 mg of GTx-758), fatal heart attack (2% of those taking 1000 mg GTx-758) and blood clots within the lung (4% of those taking 1000 mg GTx-758). 

The authors concluded that while GTx-758 treatment did not lower total testosterone levels as completely and rapidly as leuprolide, it did achieve greater decreases in levels of free testosterone. GTx-758  was also associated with a reduction in side-effects associated with low estrogen levels, but was associated with higher levels of adverse events. 

Most of the authors in this article were provided research support from the drug manufacturer, GTx-758 Inc. There is another ongoing study which is assessing the safety and effectiveness of lower levels of GTx-758 following the higher rates of serious adverse events.